Hyperlipidemia (Hyperlipoproteinaemia).pptx

Hyperlipidemia (Hyperlipoproteinaemia).pptx

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  Hyperlipidemia (Hyperlipoproteinaemia)
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  Hyperlipidemia (Hyperlipoproteinaemia) • Lipidsand cholesterol are transported through the bloodstream as macromolecular complexes of lipid and protein known as lipoproteins.
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  Hyperlipidemia (Hyperlipoproteinaemia) • Thereare four main classes of lipoprotein;- • high density lipoproteins (HDL) • low density lipoproteins (LDL) • very low density lipoproteins (VLDL) • chylomicrons
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  • A familyhistory of hyperlipidemia. • A diet high in total fat, saturated fat, or cholesterol. • Obesity Causes of hyperlipidemia
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  Causes of hyperlipidemia •Certain conditions including • Diabetes. • Renal disease. • Hypothyroidism. • Liver disease. • Cushing's syndrome (↑ blood cortisol).
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  Causes of hyperlipidemia •Certain drugs such as • Hormones or birth control pill • Corticosteroids • Isotretinoin (antiacne agent) • β blockers • Thiazides diuretics •
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  Untreated hyperlipidemia cancause (↑ risk of ) Atherosclerosis (hardening of the arteries) Heart attack Stroke (sudden unconsciousness due to cerebrovascular thrombosis, embolism or hemorrhage with varying degrees of hemiplegia).
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  Risk factors include •Advancing age • Adult men (any age) • Adult women (postmenopause) • Lack of exercise • Stress • Smoking • excessive alcohol intake
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  Function of lipoproteins(The larger the size, the lower the density) Function 1) Chylomicrons TG-rich particles Transport dietary (exogenous) TG from the intestine to liver 1) VLDL Transport endogenous TG & Cholesterol from liver to the peripheral tissues for storage and or energy production. 1) LDL Carry cholesterol to peripheral tissues 1) HDL Facilitate removal of cholesterol from peripheral tissues to liver
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  Lipoproten lipase (LPL) •Cause Degradation (lipolysis) of TGs present in VLDL and chylomicrons fatty acids and glycerol (to be stored or utilized in energy production)
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  Fredrickson classification ofPrimary hyperlipoproteinaemia (6 types) Type (Familial) Lipoprotein CH TG I (hyperchylomicronemia) Chylomicrons + +++ IIa (hypercholesterolemia) LDL ++ Not ↑ IIb (combined {mixed} hyperlipidemia). LDL+VLDL ++ ++ III (dysbetalipoproteinemia). IDL ++ ++ IV (hypertriglyceridemia) VLDL + ++ V (mixed hypertriglyceridemia) Chylomicrons + VLDL + ++
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  Management of Hyperlipidemia •Diet and lifestyle changes can help treat hyperlipidemia • Diet Changes • Restriction of caloric intake (35% as fat, 50% as carbohydrate and 15% as protein) • Restriction of cholesterol to < 300 mg/day (equivalent to 11/2 eggs) • Replace animal fats with polyunsaturated fatty acids & Increase in dietary fibers • ↑ dietary fibers (fruits & vegetables)
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  Management of Hyperlipidemia •Lifestyle Changes – Weight reduction (for overweight and obese persons). – Exercise. – Cessation of smoking. – Reduction or elimination of alcohol intake. • A combination of diet, lifestyle changes and medication may be required in some cases
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  Drug Therapy • 1-Fibric acid derivatives (Fibrates or peroxisome proliferator-activated receptor-α (PPAR α)activators agonist) • Clofibrate , • Fenofibrate , • Bezafibrate , • Etofibrate , • Ciprofibrate, • Gemfibrozil
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  Mechanism of action •Activate the nuclear peroxisome proliferator-activated receptor-α (PPAR α) which is found mainly in hepatocytes and adipocytes and functions to regulate lipoprotein metabolism. • ↓ TG level through 1-↑ fatty acid oxidation mediated through PPAR α - stimulation 2-↑ peripheral LPL (lipoprotein lipase) synthesis 3-↓ Hepatic TG synthesis
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  Mechanism of action •↓ LDL levels by enhancing its hepatic clearance. – Bezafibrate and fenofibrate are more effective than gemfibrozil and clofibrate in lowering LDL level.
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  Indications of Fibratetherapy • Indicated in clinical disorders associated with ↑ circulating TGs such as • Type IIb (↑ VLDL+LDL) mixed hyperlipidemia. • type III (↑IDL) • Types IV (↑ VLDL) hypertriglyceridemia. • Type V (↑ VLDL+CM) mixed hypertriglyceridemia.
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  Indications of Fibratetherapy • Fibrate therapy is a suitable choice for the treatment of dyslipidemia in diabetic patients who often demonstrate hypertriglyceridemia and low levels of HDL
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  Fibrate Pharmacokinetics • Allfibrates are absorbed rapidly and efficiently (> 90%) when given with a meal but less efficiently when taken on an empty stomach
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  Adverse effects ofFibrates • GIT disturbances (5-10% of patients) • Cholelithiasis (gallstone formation) due to ↑ biliary cholesterol excretion. • • Myopathy  fibrates can cause myositis especially in patients with renal insufficiency (Muscle weakness and tiredness should be evaluated)
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  Adverse effects ofFibrates • Infrequent adverse effects( ADRs) include  arrhythmias, hypokalemia,  ↑ aminotransferase, ↑ alkaline phosphatase, skin rashes, urticaria, headache, hair loss,  impotence,  myalgia, fatigue  anaemia.
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  Drug Interactions • FibratesX oral anticoagulants  (↑ anticoagulant Activity). • (Displacement reaction so ↓ anticoagulant dose) • Fibrates X oral sulphonylureas (↑ sulphonyluria action
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  Contraindications Pregnancy and lactation. Severehepatic and renal dysfunction. Pre-existing gallbladder disease.
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  2) HMG-CoA ReductaseInhibitors (Statins) • High-potency statins  Rosuvastatin and atorvastatin. • Intermediate potency statins  simvastatin and pravastatin. • Low-potency statins  lovastatin and fluvastatin. Most effective and best-tolerated agents for treating elevated LDL-C. hydroxymethylglutarate coenzyme
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  Mechanism of action •(1) Inhibition ofHydroxy Methyl Glutarate –CoA( HMG-CoA) reductase enzyme (↓ CH synthesis) • statins competitively inhibit the enzyme HMG-CoA reductase (the rate- limiting step in cholesterol synthesis) leading to » Inhibition of hepatic cholesterol synthesis » depletion of intracellular free cholesterol •
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  Mechanism of action •(2) Increase in LDL receptor (↑LDL catabolism) • Depletion of intracellular cholesterol  hepatic cell ↑ number of surface LDL receptors that can bind and remove LDL-C from blood • Statins also can enhancing the removal of LDL-C precursors (VLDL & IDL) from the circulation ↓ LDL-C levels • (3) Reduction of plasma TGs • By ↓ hepatic VLDL production and secretion. • (4) Elevation of HDL-C
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  Indications of Statins »Treatment of familial types IIa and IIb » dyslipidemic diabetic patients (↓ LDL and TGs and ↑ HDL) » Treatment of elevated LDL plasma levels either as monotherapy or with bile acid binding resins or niacin » Statins are less effective in patients with homozygous familial hypercholesterolaemia who lack LDL receptors
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  Pharmacokinetics • Absorbed afteroral administration. • Metabolism in liver • Bound to plasma protein • Statins are excreted mainly through the bile and feces (>70%) with some urinary excretion.
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  Adeverse effects • Transientelevation of serum transaminases • Myopathy (muscle weakness) and rhabdomyolysis (disintegration of muscle tissue)
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  Contraindications • Pregnancy andlactation. • Children and teenagers. • Homozygous familial hypercholesterolemia
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  3) Bile acid-bindingResins • Cholestyramine, • Colestipol, • Colesevelam
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  Mechanism of action •These are highly positively charged anion- exchange resins that bind negatively charged bile acids and bile salts in the small intestine  non-absorbable resin/bile acid complex  excreted in stool  preventing bile acids from returning back to the liver by the enterohepatic circulation •
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  Mechanism of action •↓ Hepatic bile acid  as a compensatory mechanism hepatocytes ↑ conversion of cholesterol to bile acids (essential components of bile) • The resultant ↓ intracellular cholesterol  ↑ hepatic uptake of cholesterol-rich LDL  upregulation of hepatocyte surface LDL receptors ↓ plasma LDL-C
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  Mechanism of action •Produce a modest rise in HDL-C in some patients
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  Indications • Primary chylomicronemia. •Familial hypertriglyceridemia • Relief of excess bile acid-induced pruritus in patients with biliary obstruction.
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  Adverse effects • GITeffects  constipation, bloating (flatulence) & nausea . • High-dose cholestyramine and colestipol impairs the absorption of fat-soluble vitamins (ADEK).
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  Drug Interactions • Cholestyramineand colestipol interfere with the intestinal absorption of many drugs including tetracycline, digoxin, warfarin , pravastatin, fluvastatin, aspirin, phenobarbital and thiazide diuretics
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  4) Niacin (Nicotinicacid,Vitamin B3) • Mechanism of action • Niacin ↓ hepatic TGs synthesis LPL induced lipolysis of TGs in adipose tissues Niacin ↓ hepatic VLDL-C production
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  Therapeutic Uses – Familialhyperlipidemias (↓ cholesterol & TGs). – Severe hypercholsterolemias (+ statins). – Familial dysbetalipoproteinemia (Type III) (↑lDL  ↑TGs + TC)
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  Adverse Effects • Flushing(due to cutaneous PG-mediated vasodilatation) • Dyspepsia, nausea & abdominal pain. • Uric acid retention
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  Contraindications • Pregnancy • Historyof gout (gout may occur in 20% of patients).
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  5) Cholesterol AbsorptionInhibitors (Ezetimibe)
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  Mechanism of Action •Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol ↓ ch in chylomicrons (CM) ↓ cholesterol delivery to the liver ↓ hepatic cholesterol stores  ↑ hepatic LDL receptors  ↑ cholesterol clearance from blood. •
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  Therapeutic Uses • Treatmentof hypercholesterolemia often in combination with a statin • As monotherapy in statin-intolerant patients
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  Adverse Effects • Myopathy(with or without statins). • Allergic reactions (rarely). • Hepatotoxicity
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  Contraindications • Pregnancy &lactation. • Moderate and severe hepatic insufficiency
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  6) Probucol • Probucolis a hypolipidemic drug ↓ plasma LDL-C and HDL-C. • It has minimal cholesterol lowering effects, • May act by ↓ the oxidation of LDL (Oxidized LDL is taken up by macrophages to produce foam cells and atherosclerotic plaques) • Probucol is not commonly used because it ↓ HDL-C to a greater degree than LDL-C and has been associated with ventricular arrhythmias •
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  6) Probucol • Theuse of probucol • ↓ the risk of atherosclerosis might be due to – Mainly to its anti-oxidant property – An effect of lipid lowering action
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  D-Thyroxine – ↑ LDLuptake (clearance) by ↑ LDL receptors synthesis. – It can be used in • Young patients with type IIa familial hypercholesterolemia, who do not have coronary artery disease • In whom dietary treatment and other drugs have not been successful. •
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  Neomycin • It bindsbile acids in the intestine ↑ hepatic conversion of cholesterol into bile acids.
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  Plant sterols (Phytosterols) •These agents block intestinal cholesterol uptake by competition for its absorption sites, without themselves being absorbed.
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  Fish Oils – Fishoil contains ϖ3 fatty acids • ↓ VLDL-C synthesis and improved clearance of remnant particles. • ↓ Production of arachidonic acid metabolites, ↓ platelet aggregation.
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